RAS mutations drive a large proportion of deadly human tumors but no targeted therapies have advanced to clinic. We and others have shown that certain oncogenic RAS mutations have unique biochemical properties and have shown that functional classes of RAS mutations are differentially regulated, opening the door to RAS allele-tailored treatment approaches. RAS allele-specific therapies have the potential for rapid clinical translation and would be worthwhile because (1) RAS mutation status is already routinely assessed in current clinical practice for multiple common cancers, (2) potent and selective small molecules targeting members of RAS signaling pathways, or regulators of those members are already available, and (3) RAS mutations occur frequently enough in cancer that a significant number of patients would benefit even though therapies apply to subsets of RAS mutation-positive tumors. This proposal seeks to develop direct and indirect therapeutic strategies based on the unique mode of activation and resultant signaling properties of KRAS A146T and other RAS exchange mutants. This study has translational therapy implications given that KRAS A146T is already screened for in clinical practice, but no targeted therapies currently exist.